The human CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction

The gene for cytochrome P4501A2 is constitutively expressed in the liver of vertebrates and shows induced expression when an organism is exposed to polycyclic aromatic hydrocarbons and halogenated hydrocarbons. To identify DNA elements regulating transcription of the human CYP1A2 gene, transient tra...

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Bibliographic Details
Published in:The Journal of biological chemistry 1994-03, Vol.269 (9), p.6949-6954
Main Authors: Quattrochi, L C, Vu, T, Tukey, R H
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Binding Sites
Biological and medical sciences
Carcinoma, Hepatocellular
Cell Line
Cell Nucleus - metabolism
Cytochrome P-450 CYP1A2
Cytochrome P-450 Enzyme System - biosynthesis
Cytochrome P-450 Enzyme System - genetics
DNA - metabolism
DNA-Binding Proteins - metabolism
Enzyme Induction
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - drug effects
Hominidae - genetics
Humans
Liver Neoplasms
Methylcholanthrene - pharmacology
Mice
Molecular and cellular biology
Molecular genetics
Molecular Sequence Data
Nuclear Proteins - isolation & purification
Nuclear Proteins - metabolism
Oligonucleotide Probes
Oxidoreductases, N-Demethylating - biosynthesis
Oxidoreductases, N-Demethylating - genetics
Polychlorinated Dibenzodioxins - pharmacology
Promoter Regions, Genetic
Receptors, Aryl Hydrocarbon - metabolism
Sequence Deletion
Sequence Homology, Nucleic Acid
Transcription. Transcription factor. Splicing. Rna processing
Transfection
Tumor Cells, Cultured
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Summary:The gene for cytochrome P4501A2 is constitutively expressed in the liver of vertebrates and shows induced expression when an organism is exposed to polycyclic aromatic hydrocarbons and halogenated hydrocarbons. To identify DNA elements regulating transcription of the human CYP1A2 gene, transient transfection experiments were conducted in the human hepatoma cell line HepG2. Dissection of the 5'-flanking portion of the CYP1A2 gene identified two regions that contributed to the overall induction by 3-methylcholanthrene. One region located at -2532/-2423 contains an xenobiotic-responsive element-like sequence, termed X1, that binds a nuclear 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible protein in HepG2 and wild type mouse Hepa-1 cells, but not in the Ah receptor nuclear translocation defective mouse C- mutant c4 cells. In addition, deletion of this region of the CYP1A2 gene reduces the 3-methylcholanthrene (3-MC)-initiated induction of chloramphenicol acetyltransferase activity in both promoter- and enhancer-specific constructs. The second responsive region is located at -2259/-1987. This region of the gene contains a second xenobiotic-responsive element-like element, but this element does not associate with the nuclear Ah receptor. However, there does exist several potential AP1 binding sites and a conserved TATA box. A DNA fragment from -2259/-1970 that contains these elements was shown to function as an efficient eukaryotic promoter, in addition to supporting 3-MC-induced promoter activity. These results suggest that Ah receptor-specific and promoter-specific elements regulate the expression of the human CYP1A2 gene.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(17)37466-5